A major premise underlying investigations into the etiopathology of insulin dependent (type I) diabetes in humans is that autoimmune reactions may often play a central role in the destruction of the pancreatic islet cells. However, immunological studies to test this are hampered by the unavailability of human beta cells to serve as targets in laboratory studies. Murine models of both genetically-inherited and chemically-induced diabetes offer excellent systems in which to analyze whether cells of the immune system can execute acts of autoaggression against syngeneic beta cells. The objective of this research is to demonstrate that in a particularly diabetes-susceptible strain of inbred mice (C57BL/KsJ), chronic hyperglycemic stress is sufficient to alter beta cells in such a way as to elicit their autoimmune rejection. Two experimental models will be evaluated. Treatments of C57BL/KsJ male mice with multiple "low dose" streptozotocin injections will be utilized to sensitize the mice to reject small numbers of syngeneic islets transplanted into their spleens after establishment of severe hyperglycemia. Cell-mediated and/or humoral mechanisms underlying this rejection will be clarified using standard immunological techniques. These same techniques will be employed in studies of those genetically-diabetic (db/db) mice (which constitutively express and endogenous retrovirus-like particle in response to hyperglycemia) to test the hypothesis that such rejection is initiated when glucose-marked beta cells produce and express at their surface an endogenous retroviral group-specific protein (p73) which is not recognized as "self" by the host's immune surveillance system.